The invention relates to a method of synthesizing lower alkyl 3-amino-crotonates, which are substituted at the C-4 atom by halogen and at the amino group by 1 or 2 hydrogen atoms and/or 1 or 2 C1 to C3 alkyl groups or 1 or 2 aryl groups.
Lower alkyl 3-amino-crotonates, substituted by halogen at the C-4 atom, especially lower alkyl 3-amino-4,4,4-trifluorocrotonates are used as building blocks in chemical synthesis. They can be used, for example, for synthesizing herbicidal uracil derivatives, as disclosed in U.S. Pat. No. 5,399,543.
A method of synthesizing such compounds is given by W. F. Goure in J. Heterocyclic Chem. 30 (1993), pages 71 to 80 and especially on page 75. Anhydrous ammonia is passed for a period of 1.5 hours at a temperature of 75xc2x0 to 80xc2x0 C. through methyl 4,4,4-trifluoroacetoacetate. Subsequently, the reaction mixture is kept for a further 3 hours at a temperature of 100xc2x0 C. and then cooled to ambient temperature, taken up in diethyl ether, dried, concentrated and subjected to a bulb tube distillation. The yield was 59% of the theoretical.
The thermolysis of the ammonium salt in the presence of acetic acid and ethanol is described in the Japanese patent application JP 6/321877. The European patent application EP-A-0 808 826 discloses the synthesis of trihalogen crotonates using ammonium salts as a source of amine. The ammonium salt of the ester is not formed. The formation of esters of aminocrotonic acids from NH3 and esters of acetoacetic acid or esters of trifluoroacetoacetic acid with and without solvents is disclosed in Houben-Weyl, Methods of Organic Chemistry, Volumn XI/I (1957), pages 170-175, and by Pashkevich et al. in Bull. Acad. Sci. USSR Div. Chem. Sci 35 (1986), pages 1438-1442.
It is an object of the present invention to provide a method for synthesizing crotonates, which are halogen-substituted at the C-4 atom and selected from the group comprising lower alkyl esters of 3-amino-4,4,4-trifluoro-crotonates and lower alkyl 3-amino-4,4-difluoro-4-chloro-crotonates and lower alkyl 3-amino-4,4-difluoro-crotonates, with which method these products are obtained in high yield with a high degree of purity. This objective is accomplished by the method of the present invention.
The inventive method of synthesizing crotonates, which are halogen-substituted at the C-4 atom and selected from the group consisting of lower alkyl 3-amino-4,4,4-trifluoro-crotonates, lower alkyl 3-amino-4,4-difluoro-4-chloro-crotonates and lower alkyl 3-amino-4,4-difluorocrotonates, the amino group optionally being substituted by 1 or 2 C1 to C3 alkyl groups or by aryl groups, and lower alkyl denotes methyl, ethyl, n-propyl, and i-propyl, envisions the simultaneous formation under thermolytic conditions without addition of an acid, of water and lower alkyl 3-aminocrotonates substituted by halogen at the C-4 atom, the water formed being removed from the reaction mixture, in that a thermolysis reaction is carried out starting from the ammonium salt of the corresponding lower alkyl acetoacetate substituted at the C-4 atom by halogen, and in the presence of an entraining agent for the water formed, or in that, in the absence of a solvent, inert gas is passed through the molten ammonium salt of the lower alkyl acetoacetate substituted at the C-4 atom by halogen and by these means, water formed is removed from the reaction mixture.
Accordingly, the method can be carried out according to several alternative procedures. The first alternative is explained in the following.
This alternative of the inventive method for synthesizing crotonates, which are halogenated at the C-4 atom and are selected from the group comprising lower alkyl 3-amino-4,4,4-trifluorocrotonates, lower alkyl 3-amino-4,4-difluoro-4-chlorocrotonates and lower alkyl 3-amino-4,4-difluorocrotonates, in which the amino group optionally may be substituted by 1 or 2 C1 to C3 alkyl groups or by aryl groups, is characterized in that the appropriate ammonium salt of the lower alkyl acetoacetate, substituted at the C-4 atom by halogen, is thermolyzed in the presence of an entraining agent for the water formed during the thermolysis.
Pursuant to this embodiment, lower alkyl esters of 3-amino-4,4-difluorocrotonate can be synthesized from the ammonium salt (the nitrogen may be substituted especially completely by hydrogen or by hydrogen and 1 or 2 C1 to C3 alkyl groups) of the 4,4-difluoroacetoacetate ester. Lower alkyl esters of 3-amino-4,4-difluoro-4-chlorocrotonate are synthesized correspondingly from the salt of the 4,4-difluoro-4-chloroacetoacetate. Lower alkyl esters of 3-amino-4,4,4-trifluorocrotonate are synthesized similarly.
The required esters are commercial products or can be synthesized by the reaction of ketene with trifluoroacetyl chloride, difluorochloroacetyl chloride or difluoroacetyl chloride, followed by an esterification, as described by W. F. Goure, J. Heterocyclic Chem. 30 (1993), pages 71 to 80 and especially page 72.
The inventive method can be carried out starting from the ammonium salt. For example, the ammonium salt can be synthesized in a first step. It is then thermolyzed in a second step. Pursuant to a different embodiment, the ammonium salt is synthesized in situ and simultaneously thermolyzed. This embodiment can also be carried out continuously.
Preferably, 4,4,4-trifluorocrotonates are synthesized. The invention will be described further with reference to this preferred embodiment.
The following apply generally for all the alternatives of the present invention. A catalyzing agent, such as an acid, is not required and is not added. The amine or ammonia used is added as base and not as a salt, for example, of carboxylic acids. The term xe2x80x9clower alkylxe2x80x9d denotes methyl, ethyl, n-propyl and i-propyl. xe2x80x9cArylxe2x80x9d preferably refers to phenyl.
Preferably, crotonates, which have two hydrogen atoms at the amino group, are synthesized. The synthesis of methyl 3-amino-4,4,4-trifluorocrotonate or ethyl 3-amino-4,4,4-trifluorocrotonate is especially preferred.
Entraining agents are used, which do not enter into undesired reactions with the starting materials or with the products. Aliphatic hydrocarbons, aromatic hydrocarbons or halogenated aliphatic hydrocarbons, for example, are suitable. For example, benzene or toluene can be used as entraining agent. Entraining agents which have a higher density than the water phase that forms and therefore represent the lower phase are especially preferred. Halogenated hydrocarbons, such as trichloroethylene or carbon tetrachloride, are particularly suitable. Entraining agents of higher density extract the ammonium salt, which is present in the lighter water phase in the water separator and, in this way, decrease the loss in yield, especially in the case of products that sublime.
The synthesis is carried out under conditions at which the water-entraining agent boils. For the sake of simplicity, the reaction is carried out at ambient pressure; if so desired, the reaction can, of course, also be carried out at an elevated or a reduced pressure.
Preferably, the temperature of the reaction mixture falls within the range of 80xc2x0 to 120xc2x0 C. Naturally, the temperature used also depends on the boiling point of the entraining agent.
When water is no longer collected in the water separator, the entraining agent is removed, for example, by distillation and the remaining crude crotonate is purified by vacuum distillation (for example, the vacuum of a water jet pump). Ethyl 3-amino-4,4,4-trifluorocrotonate distills at a temperature of 55xc2x0 to 57xc2x0 C.
Pursuant to a second alternative, which is described in the following, the water of reaction is carried away by an inert gas. For this embodiment of synthesizing lower alkyl 3-aminocrotonates, which are substituted at the C-4 atom by halogen and selected from the group consisting of lower alkyl 3-amino-4,4,4-trifluorocrotonates, lower alkyl 3-amino-4,4-difluorocrotonates and lower alkyl 3-amino-4,4-difluoro-4-chlorocrotonates, provisions are made to start in the absence of a solvent from a molten ammonium salt of the lower alkyl ester of acetoacetic acid, which is halogenated at the C-4 atom and, under thermolytic conditions, to bring about the simultaneous formation of water and of lower alkyl 3-aminocrotonates, halogenated at the C-4 atom and, by passing an inert gas through the molten salt, to carry away from the reaction mixture the water formed by thermolysis. The nitrogen atom may be substituted by one or two C1 to C3 alkyl groups or by aryl groups.
Lower alkyl esters of 3-amino-4,4-difluorocrotonate can be synthesized correspondingly from the ammonium salt of the 4,4-difluoroacetoacetate ester. Lower alkyl esters of the 3-amino-4,4-difluoro-4-chlorocrotonate are synthesized correspondingly from the salt of the 4,4-difluoro-4-chloroacetoacetate ester. The procedure for synthesizing lower alkyl esters of 3-amino-4,4,4-trifluorocrotonate is similar.
The required esters are commercial products or can be synthesized by the reaction of ketene with trifluoroacetyl chloride, difluorochloroacetyl chloride or difluoroacetyl chloride, followed by an esterification, as described by W. F. Goure, J. Heterocyclic Chem. 30 (1993), pages 71 to 80 and especially page 72.
The term xe2x80x9clower alkyl,xe2x80x9d denotes the methyl, ethyl, n-propyl and i-propyl group. Preferably, lower alkyl represents methyl or ethyl. xe2x80x9cArylxe2x80x9d preferably refers to phenyl.
Preferably, the thermolysis reaction is carried out at a temperature ranging from the melting point of the salt or of the reaction mixture up to a maximum of 110xc2x0 C. and especially up to a maximum of 105xc2x0 C. Higher temperatures, such as those up to 120xc2x0 C. or higher can also be used. At these higher temperatures, however, decomposition products may be formed to a slight extent. Very good results are achieved if the temperature of the reaction mixture falls within the range of 80xc2x0 C. to 95xc2x0 C. As inert gas, gases can be used, which do not react in an undesirable manner with the starting material or with the products formed. Advantageously, nitrogen, argon, helium or carbon dioxide or their mixtures are used as inert gas.
Preferably, 4,4,4-trifluorocrotonates are synthesized. The invention will be explained further with reference to this preferred embodiment.
In this variant, the inventive method can also be carried out so that initially the ammonium salt of the lower alkyl ester of the 4,4,4-trifluoroacetoacetic acid is synthesized by passing essentially anhydrous ammonia into and/or over the lower alkyl ester of the 4,4,4-trifluoroacetoacetic acid. The thermolysis, with melting of the resulting salt, can then take place in a second step, without requiring any further purification operations. The conversion and yield are quantitative. Because of its purity, the crotonate formed can be used without further purification as a starting material for the synthesis of, for example, herbicides.
Pursuant to a different embodiment of the invention, the formation of the ammonium salt of the lower alkyl ester of the 4,4,4-trifluoroacetoacetic acid and its thermolysis can also be carried out simultaneously in this variation. Appropriately, the lower alkyl ester of the trifluoroacetoacetic acid is heated, and essentially anhydrous ammonia is passed into and/or over the ester, and an inert gas is passed through the reaction mixture. For example, a tubular reactor can be used, and ammonia can be introduced at the bottom of the reactor. The ester can be introduced, for example, in the upper region of the reactor. The method can also be carried out continuously.
The phrase xe2x80x9cin the absence of a solventxe2x80x9d means that, other than the reactants, no solvent, such as ethers, esters, aromatic or halogenated hydrocarbons, are not added. Only the lower alkyl acetoacetate used, which is halogenated at the C-4 atom, can be present in excess. In this case, the ammonium salt which is formed may be present in the molten state and/or dissolved in the ester. The inventive method comprises this embodiment. The term xe2x80x9cmoltenxe2x80x9d also comprises the dissolved state of the ammonium salt in the ester educt. To complete the reaction, the thermolytic conditions can be maintained for some time after the introduction of the ammonia is ended (the time of ending the introduction of ammonia can be checked, for example, by NMR analysis). The time at which complete reaction has taken place can be ascertained by means of NMR analysis. If desired, the resulting, rather pure product can be purified further by distillation. Even if such a distillation is carried out, the yield is still remarkably high.
The products are obtained in pure form. They can be purified further by distillation. Extraction of the crude product by means of solvents, as described in the state of the art, is not necessary in working up the reaction mixture.
The inventive method enables lower alkyl 3-amino-4,4,4-trifluorocrotonates to be synthesized by a simple method in high yield and with a high purity. It is thereby surprising that the removal of water brings about advantages. The dehydrating thermolysis, namely, is not an equilibrium reaction. Otherwise, a reverse reaction would have to be observed during the aqueous working up. This is evidently not the case.
The following examples are intended to explain the invention further without limiting its scope.